In humans, psychostimulants can induce a variety of aversive subjective effects, ranging from mild forms of nervousness, dysphoria, irritability, impulsivity and suspiciousness to more serious syndromal sequela, such as anxiety, depression, anger, violence, and paranoia. While the former are evident to greater or lesser degrees even among first-time users, the latter most commonly, but not invariably, occur with repeated, chronic, and high-dose drug use. In fact, the progressive emergence of such symptoms with increasing frequency and severity over the course of chronic stimulant exposure, particularly in the case of paranoia and related psychotic symptoms, has suggested a role for sensitization mechanisms in their etiology [1]. The current R03 application is submitted in response to RFA-DA-09-016, "Behavioral Pharmacology and Genetics: Targeting Individual Differences," and seeks to collect pilot data in cocaine dependent and healthy control subjects exploring potential pharmacogenetic relationships between 1) functional genetic variation in dopamine b-hydroxylase (DBH;the enzyme that converts dopamine to norepinephrine in brain), 2) positron emission tomography (PET) measures of high-affinity binding sites on the dopamine D2 receptor (D2high), and 3) individual sensitivity to the subjectively aversive effects of psychostimulants (methylphenidate and/or cocaine). This avenue of investigation is motivated by four independent, albeit convergent lines of evidence suggesting a potentially shared mechanistic basis: 1. Homozygosity for a "very low activity" DBH polymorphism (TT at DBH C-1021T) predisposes cocaine users to paranoia as measured "in vivo" by human laboratory methods. 2. DBH "knock-out" (Dbh-/-) mice display an exaggerated sensitivity to stimulants, including a conditioned place aversion to normally rewarding doses of cocaine. 3. In vitro (homogenate binding) and in vivo (microPET) data demonstrate increases in striatal D2High in Dbh-/- mice, and 4. PET studies in healthy (non-stimulant addicted) humans point to important relationships between "unpleasant" methylphenidate effects and D2 - with higher receptor levels predicting aversion vulnerability. Thus, the current R03 will evaluate the role of genetic factors in the individual response to psychostimulants, using both behavioral pharmacologic (human laboratory) and functional brain imaging (PET neuroreceptor) methods. We hypothesize that TT homozygotes at DBH C-1021T in both groups (cocaine and healthy) will have increases in D2High as measured by [11C]PHNO PET and, in turn, that these increases will be associated with a greater predisposition to negative stimulant-induced subjective effects. PUBLIC HEALTH RELEVANCE: An individual's sensitivity to aversive drug effects is likely to be important not only in the manifestations and course of drug dependence (e.g., in experienced users) but also in the predisposition and/or progression to addiction (e.g., in inexperienced or drug-naive individuals). Thus, the identification of genetic and/or neurobiologic mechanisms underlying cocaine aversion may provide insights into addiction susceptibility, and in turn, improved treatment and/or prevention efforts.